The study of risk and resilience for posttraumatic stress disorder (PTSD) has been greatly enhanced by examining the role of genetics as well as early life environment. Studies from our group indicate that polymorphisms in the FKBP5 gene may be associated with vulnerability for PTSD. Notably, PTSD cannot develop in the absence of an environmental stressor;early life trauma in particular appears to exponentially increase risk for PTSD development. Gene by environment interaction studies have offered a logical approach to investigating vulnerability to this disorder, but offer an incomplete model for understanding this risk. The exploration of endophenotypes is a novel and pragmatic way to understand the complex path from genes to disease occurrence. Specific alterations in patterns of neural function have been associated with maltreatment and PTSD, and are attractive endophenotypic candidates in understanding PTSD risk. When viewing emotionally-salient cues or engaging in tasks that require attention, individuals with PTSD have demonstrated altered activity in brain regions implicated in cognitive control and emotion regulation, including the medial prefrontal cortex (mPFC), the dorsolateral prefrontal cortex (dlPFC), and the amygdala. Alterations in neural response the mPFC, dlPFC and amygdala in response to tasks involving attention to emotion may serve as functional endophenotypes. Three white matter (WM) tracts that connect these structures are likewise valuable targets for exploration as candidate structural endophenotypes, given that the integrity of these paths is critical for efficient communication among these different cortical regions. The arcuate fasciculus (AF) the cingulum bundle (CB), the corpus callosum (CC), have been highlighted in studies of maltreated children and mixed populations of adults with PTSD. Overall, it appears that decreased WM integrity in the AF, CB, and CC represent important structural endophenotypes in understanding genetic risk for PTSD. Thus, the proposed study is designed to examine potential functional and structural neural endophenotypes for PTSD. Specifically, I plan to examine associations among FKBP5 genetic status, childhood maltreatment history and neural response in the dlPFC, mPFC, and amygdala (using functional MRI), in individuals with variable PTSD symptoms during attention to trauma-related cues. I will also examine of associations among FKBP5 genetic status, childhood maltreatment history, and WM integrity in the AF, CB, and CC (using Diffusion Tensor Imaging) in individuals with variable PTSD symptoms. PUBLIC HEALTH RELEVANCE: Genetics and early-life trauma are clearly important contributors to the development of PTSD, but the link between genotype and phenotype is not straightforward in PTSD research. The exploration of intermediate biological factors, or endophenotypes, can help to explain the complex path from genes to PTSD risk. Thus, this study is designed to investigate associations between genetic profiles, maltreatment, neural endophenotypes, and PTSD symptoms as a way to expand current scientific knowledge of how genetic variants contribute to PTSD vulnerability.